We are utilizing a genetically engineered mouse model of pancreatic cancer with tissue specific expression of mutant-KRAS and -P53 gene. Crossbreeding of LSL-Kras G12D, p53 R172 H and Pdx-1-Cre generates the triple mutants, commonly known as KPC mice, which develop PDAC with a median survival of approximately 5 months and almost 100% mortality by 12 months. The KPC mice faithfully recapitulate the development and progression of human PDAC. To determine the role of MIF and NO in PDAC, we have further engineered this model to generate both the iNOS- and MIF-deficient KPC models. The summary of our progress in this project includes:1) Generation of iNOS- and MIF-deficient mouse model of pancreatic cancer2) iNOS-deficiency enhances the survival in mice with pancreatic cancer.In this ongoing study, we are currently investigating the mechanism of NO-mediated tumor progression. Furthermore, based on our investigation of MIF showing its association with disease aggressiveness in human PDAC and its mechanistic role in disease progression and metastasis, we are using MIF-deficient pancreatic cancer mouse model to determine its role in tumor development and progression and to assess its potential as a candidate therapeutic target.